As a method of synthesizing captopril of the above formula (1) from a substrate compound of the above general formula (2) [hereinafter referred to as substrate compound (2)], experimental examples of the reaction under basic conditions using an alkali metal hydroxide or the like have heretofore been reported (e.g. U.S. Pat. No. 4,105,776 and Japanese Kokai Publication Hei-3-169856 and Hei-5-221966).
As can be understood from the following reaction schema, any reaction under such basic conditions is a stoichiometric reaction in which at least 3 moles of an alkali metal hydroxide, for instance, may be consumed for each mole of substrate compound (2) (Japanese Kokai Publication Hei-3-169856). ##STR4##
wherein R is as defined hereinbefore; M represents an alkali metal ion such as Na.
The above reaction is disadvantageous in that it gives rise to a disulfide of the following formula (7) as a byproduct contaminating the product captopril. ##STR5##
Once the disulfide of formula (7) is by-produced, it takes much time and labor to remove the byproduct [Chemical Pharmaceutical Bulletin, 30 (9), 3139-3146, 1982; Chinese Patent 1034920A].
It is known that the by-production of the disulfide of formula (7) and other impurities is chiefly attributable to oxidation reactions involving molecular oxygen [Shigeru Ohba: Organosulfur Chemistry, Reaction Mechanisms, Kagaku Dojin).
For suppressing by-production of said disulfide of formula (7), the production of captopril from substrate compound (2) is generally carried out in an inert atmosphere such as nitrogen gas, helium gas, argon gas, or hydrogen gas [e.g. Japanese Kokai Publication Hei-5-221966].
However, the use of such an inert atmosphere for the reaction is a mere negative contrivance designed to prevent infiltration of oxygen and once oxygen has found its way into the reaction system, the by-production of said disulfide of formula (7) can hardly be inhibited.
It is difficult to completely eliminate oxygen and any residual oxygen has a serious adverse effect. For example, in the reaction giving rise to said byproduct disulfide of formula (7) from captopril and molecular oxygen, one mole of oxygen may consume as many as 4 moles of captopril as shown below (Japanese Kokai Publication Hei-3-169856). ##STR6##
In the above reaction schema, R.sup.1 represents a captopril residue of the following formula. ##STR7##
Furthermore, the captopril obtained by the above reaction may contain N-(.alpha.-methyl-.beta.-(.beta.-methyl-.beta.-hydroxycarbonyl) ethylthiopropionyl)-L-proline of the following formula (8) as an onerous impurity. ##STR8##
Thus, N-(.alpha.-methyl-.beta.-(.beta.-methyl-.beta.-hydroxycarbonyl) ethylthiopropionyl)-L-proline of formula (8) can hardly be removed by a purification procedure and its elimination calls for a great deal of effort (Japanese Kokai Publication Hei-5-221966).
The investigation made by the inventors of the present invention (as disclosed in Japanese Patent Application Hei-7-286886) revealed that this N-(.alpha.-methyl-.beta.-(.beta.-methyl-.beta.-hydroxycarbonyl)ethylthiopr opionyl)-L-proline of formula (8) is derived from the compound of the following general formula (3) and/or the compound of the following formula (4) which are/is present concomitantly with said substrate compound (2) in the reaction system for synthesis of captopril. ##STR9##
wherein R is as defined hereinbefore; n represents an integer of 2 to 4. ##STR10##
Therefore, it is important to inhibit or suppress the conversion of the compound of general formula (3) [hereinafter referred to as compound (3)] and/or the compound of formula (4) [hereinafter referred to as compound (4)] to said N-(.alpha.-methyl-.beta.-(.beta.-methyl-.beta.-hydroxycarbonyl) ethylthiopropionyl)-L-proline of general formula (8).
The above compound (3) and/or compound (4) is readily by-produced in the course of the synthesis of said substrate compound (2) by, for example, the Schotten-Baumann reaction between an acid halide of the following general formula (5) and L-proline of the following formula (6) under basic conditions. ##STR11##
wherein R is as defined hereinbefore; X represents halogen. ##STR12##
It has been discovered that in the course of cleavage of RCO under basic conditions, the byproduct compound is converted to the above-mentioned compound of formula (8).